Liquid feeding device for the generation of droplets

ABSTRACT

The present invention provides, inter alia, for a liquid feeding device for the generation of droplets, in particular for the use in a process line for the production of freeze-dried particles, with a droplet ejection section for ejecting liquid droplets in an ejection direction, the droplet ejection section comprising at least one inlet port for receiving a liquid to be ejected, a liquid chamber for retaining the liquid, and a nozzle for ejecting the liquid from the liquid chamber to form droplets, wherein the liquid chamber is restricted by a membrane on one side thereof, the membrane being vibratable by an excitation unit, wherein the longitudinal axis of the liquid chamber is tilted relative to the longitudinal axis of the nozzle, and/or the liquid feeding device further comprises a deflection section for separating the droplets from each other by means of at least one gas jet, wherein the deflection section gas jet intersects perpendicular with an ejection path of the liquid ejected from the liquid chamber.

RELATED APPLICATIONS

This application is a Continuation U.S. patent application Ser. No.15/328,068 filed on Jan. 23, 2017, which is a National Phase of PCTPatent Application No. PCT/EP2015/066583 having International filingdate of Jul. 20, 2015, which claims the benefit of priority of EuropeanPatent Application No. 14002529.7 filed on Jul. 21, 2014. The contentsof the above applications are all incorporated by reference as if fullyset forth herein in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The invention relates to the generation of droplets, in particular to beused for the production of freeze-dried pellets as bulkware, wherein aliquid feeding device is applied for the generation of droplets for theproduction of freeze-dried particles by means of a respective processline for droplet generation and freeze congealing of liquid droplets toform pellets.

The production method generally referred to as freeze-drying, also knownas lyophilization, is a process for drying high-quality products suchas, for example, pharmaceuticals, biotechnology materials such asproteins, enzymes, microorganisms, and in general any thermo- and/orhydrolysis-sensitive material. With freeze-drying, the frozen product isusually dried via the sublimation of ice crystals into water vapor, i.e.via the direct transition of water content from the solid phase into thegas phase. Freeze-drying is often performed under vacuum conditions butworks generally also under atmospheric pressure.

Application examples for freeze-drying processes in the pharmaceuticalarea comprise drying drugs or APIs (Active Pharmaceutical Ingredients),API formulations, hormones, peptide-based hormones, monoclonalantibodies, blood plasma products or derivatives, vaccines or otherinjectables and in general substances which otherwise would not bestable over a required time span. Removing the water prior to sealingthe product in vials or other appropriate containers for preservingsterility results in that the product can be stored and shipped, andpermits that the product can later be reconstituted by dissolving theproduct in an appropriate medium, such as water or the like, prior toadministration, e.g., by intradermal or intramuscular injection.

Design principles for freeze-dryer devices are well-known in the presenttechnical field. For example, tray-based freeze-dryers comprise one ormore trays or shelves within a (vacuum) drying chamber. Vials can befilled with the product and arranged on a tray, and then the tray withthe filled vials is introduced into the freeze-dryer and the dryingprocess is started.

Process systems combining spray-freezing and freeze-drying are alsowell-known in the present technical field. For instance, U.S. Pat. No.3,601,901 describes a highly integrated device comprising a vacuumchamber with a freezing compartment and a drying compartment. Thefreezing compartment comprises a spray nozzle on top of an upwardlyprojecting portion of the vacuum chamber. The sprayed liquid is atomizedand rapidly frozen into a number of small frozen particles which falldownwardly within the freezing compartment to arrive at a conveyorassembly. The conveyor advances the particles progressively forfreeze-drying in the drying compartment. When the particles reach adischarge end of the conveyer, they are in freeze-dried form and falldownwardly into a discharge hopper.

As another example, WO 2005/105253 describes a freeze-drying apparatusfor fruit juice, pharmaceuticals, nutraceuticals, tea, and coffee. Aliquid substance is atomized through a high-pressure nozzle into afreezing chamber and reduced in temperature to below its eutectictemperature, thereby inducing a phase change of liquids in the liquidsubstance. A co-current flow of cold air freezes the droplets. Thefrozen droplets are then pneumatically conveyed by the cold air streamvia a vacuum lock into a vacuum drying chamber and are further subjectedto an energy source therein to assist sublimation of liquids as thesubstance is conveyed through the chamber.

Many products to be freeze-dried are compositions comprising two or moredifferent input agents or components which are mixed prior tofreeze-drying. Thus, a composition is mixed with a predefined ratio andis then freeze-dried and filled into vials for shipping. A change in themixing ratio of the composition after filling into the vials ispractically not feasible. The mixing, filling and drying processestherefore cannot normally be separated.

WO 2009/109550 A1 discloses a process for stabilizing an adjuvantcontaining a vaccine composition in dry form. It is proposed to separateif desirable the drying of the antigen from the drying of the adjuvant,followed by blending of the two before the filling or by sequentialfilling. Specifically, separate micropellets comprising either theantigen or the adjuvant are to be generated. The antigens micropelletsand the adjuvants micropellets are then blended before filling intovials, or are directly filled to achieve the desired mixing ratio onlyat the time of blending or filling. Further it is possible to improvethe overall stability, as the stabilizing formulations can be optimizedindependently for each component. The separated solid states allow toavoid interactions between the different components throughout storage,even at higher temperature.

Products such as to be found in the pharmaceutical or biotechnology areaoften have to be manufactured under closed conditions, i.e., they haveto be manufactured under sterile conditions and/or under containment.Thus, a process line intended for a production under sterile conditionshas to be adapted such that no impurities can enter and contaminate theproduct. Further, a process line adapted for a production undercontainment has to be adapted such that neither the product, elementsthereof, nor auxiliary material can leave the process line and enter theenvironment. Here, one of the critical components for such a processline, in particular for the sterile manufacture of lyophilizedmicrospheres, is the nozzle device serving to generate droplets to befreeze-dried, sometimes also referred to as spray nozzle or prillingnozzle. In particular, the nozzle can define in a very early stage ofthe process parameters of the product quality like particle size andparticle size distribution. Due to this, the nozzle is a very importantcomponent of the bulk freeze drying process and a specific developmentarea due to the number of parts of the nozzle, which are influencing theproduct quality significantly.

The detailed description of an example of such a prilling nozzle can befound in U.S. Pat. No. 6,458,296 B1, in which a nozzle is providedinside a reactor and consists of a carrier plate with a depressiondefined by a circular peripheral wall a bore extending from the centerpoint of its bottom. The bore opens in a recess for accommodating anozzle. Associated with the depression is a pressure ring fixing adiaphragm made of silicone and a seal, such that a pulsation chamber isprovided by the diaphragm and the depression. The diaphragm carries adisk magnet which is fixed to the diaphragm, for example by gluing, andan electrical coil is suspended at a spacing with respect to the diskmagnet, wherein alternating current flows passing through the coilgenerate alternately positive and negative magnetizations. The thusgenerated magnetic waves act on the disk magnet and cause it to vibratetogether with the diaphragm, resulting in a resonant excitation of thesame. In the pulsation chamber, a liquid is introduced and urged throughthe nozzle by the generated vibrations, leaving the nozzle in form of aliquid jet which breaks apart into droplets due to the surface tension,thereby generating ejected droplets, which is known as so called“laminar jet break up”. As long as no resonance frequency is initiated,the droplet size distribution is broad. The resonance frequency,however, leads to monosized droplets. Thereafter, the droplets passthrough a central aperture of a metal ring connected to a high-voltagesource, wherein the ejected droplets penetrate into an electrical fieldwhich is built up between the metal ring and the nozzle such that acharge flux occurs in the direction of the nozzle, providing theseparated droplets with a similar electrostatic charge causing mutualrepulsion of the droplets for separating the droplets from each other.

However, the solution as proposed in U.S. Pat. No. 6,458,296 B1 exhibitscertain undesired disadvantages, such as a lack of suitability for CiP(“Cleaning in Place”) and/or SiP (“Sterilization in Place”)requirements, a weak fixing of the magnet on the diaphragm, leading toeasy separation of the magnet, for example caused by heat, a highflexibility of the membrane resulting in the need to stabilize themembrane during sterilization, difficult mounting of the entirestructure, a nozzle design intended for sterilization in an autoclaveafter disassembling the entire structure, no possibility of deaeration,i.e. gas-ventilation, without removing the nozzle, or sticking of theelectrostatically charged droplets at the reactor walls or othercomponents inside the reactor, resulting in undesired waste product.Therefore, there is a need for a redesigned prilling nozzle deviceresolving the cited disadvantages of the known prior art, focusing onimproved reproducibility of droplet generation, improved design for CiPand SiP requirements, use of defined GMP (“Good Manufacturing Practice”)compatible materials, improved integration of droplet counting, andimproved deflection system, i.e. preferably avoiding electrostaticcharging that puts an impediment to further particle handling.

As further known prior art in regard to nozzle technique and dropletgeneration, EP 1 550 556 A1 describes an inkjet recording apparatus forjetting a droplet to a base member, wherein the apparatus comprises insome embodiments a liquid solution supplying section with a liquidsolution chamber. Inside the chamber, a piezo element is arranged, and adriving voltage power source is provided for applying a driving voltagefor changing the shape of the piezo element in order to achieve thejetting of a droplet to the outside of the chamber through a nozzle.

Now, in order to evaluate if a certain nozzle design provides useablenozzle functionality, droplets need to be identifiable over a distanceof preferably 200 mm, wherein a variation of about 500 Hz should stillbe sufficient to provide droplets over the whole distance but ofdifferent droplet size, which indicates the robustness of the dropletformation by the respective nozzle design. The liquid feeding device ofthe present invention as described below fulfills these requirements.

SUMMARY OF THE INVENTION

In view of the above, the present invention provides a liquid feedingdevice for the generation of droplets, in particular for the use in aprocess line for the production of bulkware of freeze-dried particles.In detail, the present invention provides such a liquid feeding devicecomprising a droplet ejection section for ejecting liquid droplets in anejection direction, wherein the droplet ejection section comprises atleast one inlet port for receiving a liquid to be ejected, also referredto as liquid infeed, a liquid chamber for retaining the liquid, and anozzle for ejecting the liquid or liquid jet from the liquid chamber toform droplets. Here, the liquid chamber is restricted by a membrane onone side thereof, wherein the membrane is vibratable by an excitationunit. The liquid feeding device can comprise a deflection section forseparating the droplets from each other by means of at least one gasjet. Further or alternatively, the liquid chamber can be tilted comparedto the horizontal in a way such that the longitudinal axis of the liquidchamber is tilted relative to the longitudinal axis of the nozzle.Moreover, the deflection section gas jet intersects perpendicular withan ejection path of the liquid ejected from the droplet ejection sectionresulting in separate droplets, also referred to as droplets ejectedfrom the droplet ejection section. With such a structure of the liquidfeeding device, the liquid is introduced through the liquid infeed andurged through the liquid chamber and the nozzle by the generatedvibrations, leaving the nozzle in form of a liquid jet which breaksapart into droplets due to the surface tension, thereby generatingejected droplets downstream the nozzle. Here, it is to be noted that, incertain embodiments, one may implement a deflection section based on anelectrostatic appliance or the like as an addendum or an alternative tothe deflection section for separating the droplets from each other bymeans of a gas jet. Deflection sections based on electrostatic applianceor the like are known in the art. It is to be noted that the ejectiondirection is to be understood as a direction in which the liquid orliquid jet and, further downstream, the droplets are ejected out of thenozzle, i.e. a direction along or parallel to the longitudinal axis ofthe nozzle body, and an ejection path is to be understood as the coursethat the liquid or, further downstream, the droplets travel downstreamof the nozzle. In the case that the nozzle is directed verticallydownwards towards the ground and the droplets are only affected bygravity, the ejection direction and the ejection path of the dropletscoincide, both being directed towards the ground. Now, by means of theat least one gas jet of the deflection section, the droplets can beseparated from each other in order to avoid coalescence of the dropletsprior to freezing and to improve the heat transfer by spreading thedroplets. The gas jet can exit a gas access port provided in thedeflection section, wherein the gas used for the gas jet is preferablysterile filtered gas.

In order to achieve the vibrations of the membrane, the excitation unitpreferably comprises a combination of a permanent magnet separablyattachable to the membrane opposite the liquid chamber and anelectromagnetic coil for actuating the permanent magnet. Here, avertical adjustment of the electromagnetic coil support is necessary toavoid any tilting of the permanent magnet and to ensure a coherentcontact to the membrane. A damping element can be provided around thepermanent magnet and between the same and the electromagnetic coil forachieving a damping effect between the magnet and the coil, preferablywherein the damping element is made out of silicone, with such molds orshapes of the damping element that the electromagnetic coil and themagnet all have defined positions, and wherein the coil can be made outof copper. The damping element, also referred to as damper, can increasethe displacement of the magnet, wherein the damping element preferablyaccommodates the magnet in a way that it can be just mounted centricallyto the electromagnetic coil to avoid any tilting of the magnet.Preferably, medium sized magnets are to be used.

Now, as to the function of the excitation unit, the electrical frequencyapplied to the electromagnetic coil is transformed into mechanicalvibration of the magnet, wherein the applied frequency preferably rangesfrom 800 Hz to 10.000 Hz, more preferably from 1.300 Hz to 3.500 Hz. Themechanical vibration of the magnet then needs to be transferred furtherto the membrane, which is in direct contact with the liquid out of whichdroplets have to be generated. Here, the magnet preferably needs to bein contact with the membrane, for example by means of a magnetic contactor the like. In this regard, it is preferable that the membrane is astainless steel membrane, i.e. made of the type of stainless steel thathas magnetic properties, such as 1.4028 steel or AM 350 steel,preferably GMP compatible, with a preferred thickness of about 100 μm. Astainless steel membrane, for example welded on a flange, providesenough flexibility in order to achieve a precise vibration inside theliquid jet. With the vibrating membrane, a controlled intrinsicvibration can be provided to the liquid jet, such that the liquid jetleaving the nozzle is broken into equally sized droplets by asuperimposed mechanical vibration. As an alternative, the mechanicalvibration transferred to the membrane may also be generated by otherkinds of excitation units, such as units applying a piezo actuator, amechanical eccentric wheel, or the like. A vertical adjustment of asupport of the electromagnetic coil can be advantageous to avoid anytilting of the magnet and to ensure a coherent contact between themagnet and the membrane.

Further, the deflection section can comprise at least one deflectiontube for emitting the at least one gas jet, wherein the at least onedeflection tube protrudes from a main body of the deflection section inthe ejection direction of the droplets. Here, the deflection sectioncomprises a main body and the at least one deflection tube whichprojects from the main body of the deflection section parallel to theejection direction of the droplets, i.e. the ejection path of thedroplets, such that the deflection tube is basically provided collateralto the droplets ejection path such that the longitudinal axis of thedeflection tube and the droplet ejection path are aligned in the sameplane. Further, the at least one gas jet emitted from the deflectiontube is provided in a manner such that the gas jet is directed towardsthe droplets, thereby intersecting with the droplet ejection path,preferably perpendicular, i.e. at an angle of about 90°. Moreover, inview of the droplet ejection path, the ejected droplets can pass througha recess provided in the main body of the deflection section in order toarrive in the vicinity of the deflection tube. Here, the recess can be acentral through-hole the main body of the deflection section, extendingthrough the same, through which the droplets pass on their way to theintersection point with the gas jet.

Alternatively or additionally, the deflection section comprises at leasttwo deflection tubes arranged opposite to each other. Here, thedeflection section comprises a main body and the two deflection tubesproject from the main body of the deflection section parallel to theejection direction of the droplets, i.e. the ejection path of thedroplets, such that the deflection tubes are both basically providedcollateral, i.e. parallel to the droplets ejection path such that therespective longitudinal axis of the deflection tubes and the dropletejection path are aligned in the same plane.

Further, the at least one gas jet emitted from each of the twodeflection tubes is provided in a manner such that the respectivelyemitted gas jet is directed towards the droplets, thereby intersectingwith the droplet ejection path, preferably perpendicular, i.e. at anangle of about 90°.

Due to the arrangement of the two deflection tubes opposite to eachother across the droplet ejection path, preferably with the samedistance to the droplet ejection path, the emitted gas jets meet eachother right at the droplet ejection path of the droplets ejected fromthe droplet ejection section, thereby intersecting with the same.

Alternatively or additionally, the deflection section comprises fourdeflection tubes, wherein each two of the four deflection tubes can bearranged opposite to each other. Here again, the deflection sectioncomprises a main body and the four deflection tubes project from themain body of the deflection section parallel to the ejection directionof the droplets, i.e. the ejection path of the droplets, such that thedeflection tubes are both basically provided collateral, i.e. parallelto the droplets ejection path such that the respective longitudinal axisof each two of the four deflection tubes arranged opposite to each otherand the droplet ejection path are aligned in the same plane. Further,the at least one gas jet emitted from each of the four deflection tubesis provided in a manner such that the respectively emitted gas jet isdirected towards the droplets, thereby intersecting with the dropletejection path, preferably perpendicular, i.e. at an angle of about 90°.Thereby, the at least four gas jets preferably intersect with each otherat the droplet ejection path. This allows that the ejected dropletsmight also enter the deflection section de-centered from thelongitudinal or vertical axis, i.e. the droplet ejection path, whichmakes a droplet deflection function more robust, resulting in that ahigher resistance against vertical deviations can be achieved.

Moreover, in view of the droplet ejection path, the ejected droplets canpass through a recess provided in the main body of the deflectionsection in order to arrive in the vicinity of the deflection tubes.Here, the recess can be a central through-hole of the main body of thedeflection section, through which the droplets pass on their way to theintersection point with the gas jets. The central through hole, alsoreferred to as a transition zone for the droplets or pre-deflectionzone, can be provided as a straight bore hole in a cylindrical form.However, with a straight transition zone, it becomes possible thatturbulences may cause a deposition of droplets in horizontal or verticalareas that accumulate and coalesce into larger droplets, i.e. so calleddripping, which deteriorates product quality and yield. Alternatively,the central through-hole can be provided as a conical through-hole, withan increasing diameter in the direction towards the deflection tubes.Here, the opening of the diameter of the conical shape is preferablychosen to avoid any deposition of small droplets, so called satellites,in the pre-deflection zone. After leaving the conical zone, the dropletsget separated from each other by deflection gas jets. In the main bodyof the deflection section, the gas for the gas jets is guided in achamber inside the main body around the transition zone, from where itis finally transferred into the vertical deflection tubes.

The precision requirements for the deflection gas jets are high sincethey have to meet exactly in the center between each other where thedroplets fall downwards. Thus, since the emitted gas jets from the twodeflection tubes being arranged opposite to each other meet exactly atthe droplet ejection path, a separation of the droplets from each otheris achieved, resulting in a desired distribution of the monosizeddroplets without the risk of droplets interfering with each other, forexample by merging into one undesired combined droplet of twice the massand size. In order to achieve an optimum droplet distribution, eachdeflection tube comprises at least two gas jet outlet ports in the formof lateral openings in the deflection tubes, preferably three gas jetoutlet ports, for example with a diameter of about 0.4 mm.

Furthermore, each deflection tube has an inclined tip end, wherein thegas jet outlet port at the tip of the respective deflection tube, i.e.the lowest deflection opening is positioned in the lowest position andconnects with the tube interior at its edge in order to drain the entiredeflection tube during CiP and SiP processes. Here again, the precisionrequirements for the gas jet outlet ports are high since the gas jetshave to meet in the center at the droplet ejection path. In general, thedeflection by gas uses preferably 0.1 m³/h−0.3 m³/h, further preferably0.2 m³/h of deflection gas per outlet port.

In accordance with a further preferred implementation of the presentinvention, the droplet ejection section comprises at least one outletport besides the at least one inlet port, the liquid chamber and thenozzle. Preferably, the at least one outlet port, also referred to asliquid outfeed, is arranged at an outer circumference of the liquidchamber, contrary to the at least one inlet port, which is preferablyarranged near the center of the liquid chamber in the vicinity of thenozzle. Here, as mentioned above, the longitudinal axis of the liquidchamber can be tilted relative to the longitudinal axis of the nozzle,preferably in a way that the at least one outlet port is provided at thehighest level of the liquid chamber, wherein the longitudinal axis ofthe liquid chamber thus coincides with the ejection direction of theliquid. This means that the liquid chamber which generally has a largerlateral dimension than longitudinal dimension is provided in an inclinedmanner such that the liquid chamber will be filled by liquid enteringfrom the at least one inlet port until it reaches the at least oneoutlet port at the higher level or higher position, thereby ensuringthat sufficient liquid is provided to the nozzle for ejection. In orderto avoid waste of excessive liquid in the liquid chamber by releasingthe same through the outlet port or in order to avoid a breach ofsterile conditions, a blocking means can be provided subsequently to theoutlet port, such as a check valve, a shut-off valve or the like. Withthe described inclination of the entire liquid chamber, the liquidcarrying cavity is self draining and self-venting, i.e. self-deaerating,in order to avoid any gas bubbles that would change the vibrationproperties. Hereto, it is to be noted that liquids are non compressible,whereas gas bubbles are compressible, therefore the existence of gasbubbles inside the liquid chamber would be highly disadvantageous sincethe vibration work would be absorbed by the gas bubbles.

The at least one outlet port, which can also be referred in functionalterm to as a bypass opening, however, can not only serve for drainage ofexcessive liquid to be ejected from the liquid chamber but can primarilyserve for discharge of SiP fluid and/or CiP fluid introduced through theat least one inlet port into the liquid chamber. Here, it is to be notedthat the drainage of excessive liquid to be ejected can compromise asterile application of the liquid feeding device in that an open outletport might violate sterile conditions of the same. Therefore, a drainagefunction of the liquid chamber by means of the outlet port might be onlyrelevant or desired when using the liquid feeding device of theinvention not under sterile conditions. In regard of the dischargefunction of SiP fluid and/or CiP fluid, it is noted that, since thecross section of the outlet port is larger than the orifice of thenozzle, it becomes possible to feed a larger amount of SiP fluid or SiPfluid through the liquid chamber and thereby through the dropletejection section, resulting in a faster and more effective way to cleanor sterilize the droplet ejection section (i.e. the at least one inletport, the liquid chamber, the at least one outlet port and the nozzle)compared to a structure where the nozzle is the only possibility fordrainage of any fluid inside the liquid chamber. In other words, theprovision of the outlet port allows higher cleaning liquid flows andhigher sterilization fluid flows, for example saturated steam flows.

In accordance with the present invention, the droplet ejection sectioncan comprise an actuation portion and a nozzle portion, wherein theactuation portion comprises at least the excitation unit, and whereinthe nozzle portion comprises at least the membrane, the at least oneinlet port, the liquid chamber and the nozzle. Furthermore, inaccordance with above, the nozzle portion can further comprise the atleast one outlet port. Moreover, the nozzle portion can comprise anozzle portion main body and a nozzle body which is provided separatelyfrom the nozzle portion main body. In doing so, it is possible tomanufacture the nozzle portion main body and the nozzle body separatefrom each other, i.e. it becomes possible to establish the nozzlechannel in the nozzle body separately from the nozzle portion main body,for example by the means of drilling the orifice channel into the nozzlebody centrically on a turning lathe or the like. Thereby, high precisionrequirements of the drilling of the nozzle channel can be achieved,which is necessary for implementing straight droplet ejection jet fromthe orifice and for preventing a tilted droplet ejection jet. After thedrilling of the orifice channel, the nozzle body in the form of aninsert can be permanently installed in a central through-hole providedin the nozzle portion main body, wherein the liquid chamber and theoutside of the droplet ejection section are connected by the nozzlechannel. Here, the installing of the nozzle body insert into the nozzleportion main body can be achieved by laser welding or the like. Thus, anozzle function with a vertical droplet ejection jet can be achieved bythe described two-part system consisting of nozzle body and nozzleportion main body. Here, precise adjustment is necessary to ensure thevertical orifice. The length of the orifice channel is preferablybetween 0.5 mm to 2.0 mm, more preferably between 0.5 mm to 1.0 mm, andthe diameter of the nozzle orifice preferably lies within a range of 100μm to 1000 μm, further preferably within a range of 120 μm to 600 μm,more preferably about 300 μm. Here, since half of the desired dropletdiameter can be assumed as the corresponding nozzle orifice diameter, adesired pellet size of approx. 600 μm should be achieved by an orificediameter of approx. 300 μm. The deaeration connection as described aboveavoids that gas bubbles are sticking in the nozzle.

In order to be able to provide an airtight closure of the liquid chamberon the side of the membrane, the same is welded to the nozzle portion ofthe droplet ejection section, preferably by laser welding or the like.Here, the membrane can also be welded into a separate flange which isprovided separately from the nozzle portion in order to be able todisassemble and inspect all the single components. The welding of themembrane is reproducible and will lead to the same displacement evenwith a different product. In general, in view of the above describedstructure of the actuation portion comprising the excitation unit with acombination of the permanent magnet separably attachable to themembrane, the electromagnetic coil and the damping element, the mountingof the entire design needs to ensure that all these components are inclose contact. In practice, this is achieved by putting all thecomponents in a suspended, higher position and fixating them by means ofat least one positioning screw, then loosening the positioning screw andallowing the components to have magnetic contact. By this, asufficiently defined allocation of forces is achieved. The positioningscrew has to be designed such that the forces induced by the screw donot interfere with the strictly vertical alignment of all components,which can be the case in the known prior art.

In accordance with a further preferred implementation of the presentinvention, the liquid feeding device further comprises a CiP/SiP sectionbeing arranged between the droplet ejection section and the deflectionsection for providing CiP fluid and/or SiP fluid to the parts of theliquid feeding device subsequent to the droplet ejection section. Inthis section, a lateral access for cleaning liquid and steam isprovided. Here again, the section is provided with a centralthrough-hole for allowing the ejected droplets still in the form of adroplet ejection jet to pass through, wherein the droplet ejection jetleaving the nozzle orifice transforms by means of the resonancefrequency vibrations from the membrane into separate, discrete liquidsections which take the shape of a perfect sphere due to superficialtension of the ejected liquid. The height of the CiP/SiP section, i.e.the length of the through-hole therein is preferably in the range of 20mm to 50 mm, more preferably 30 mm to 40 mm. Only after the CiP/SiPsection, separate droplets are available.

As to the further structure of the liquid feeding device of the presentinvention, the liquid feeding device preferably further comprises adroplet counting section for counting the ejected droplets, wherein thedroplet counting section can be provided before the deflection sectionin the ejecting direction of the droplets, i.e. in between the CiP/SiPsection and the deflection section. The droplet counting sectionpreferably comprises a droplet counting means, for example an opticallycounting means, which can be implemented by a glass segment or glasstube and ports for fibre optics or the like, wherein the fibre opticsserve for counting of the droplets by means of an optical sender and anoptical receiver. In particular, the glass tube can be introduced as aglass cylinder integrated into a flange that carries opening ports totake up a light emitting sender and a respective receiver forregistering droplets that pass there in-between. The droplet countingsection allows to count each single droplet and, thereby, to evaluate ifthe counted number corresponds to the estimated ejected dropletsgenerated by the frequency of the vibration of the membrane. If this isthe case, it can be determined that the droplet generation is asintended, whereas a deviating result can be taken as a signal for amalfunction, resulting in an alarm or the like.

In general, in view of the above described structure of the liquidfeeding device of the present invention, including all the differentsections, the mounting of the entire design needs to ensure that allthese sections are in vertical alignment, in particular in order toachieve the intersection of the ejected droplets with the deflection gasjets. In practice, this is achieved by different centering means, forexample by means of centering bores and respective centering protrusionsat the single sections.

According to a further aspect of the invention, a freezing chamber of aprocess line for the production of freeze-dried particles is provided,preferably for the pharmaceutical field, which freezing chambercomprises a liquid feeding device as described above for the generationof droplets to be fed into the freezing chamber. Further, according toanother aspect of the invention, a process line for the production offreeze-dried particles is provided by the present invention, comprisingsuch a freezing chamber.

The above mentioned particles can comprise, for example, pellets and/orgranules. The term “pellets” as used herein may be understood aspreferably referring to particles with a tendency to be spherical.Pellets with sizes in the micrometer range are called micropellets.Accordingly, micropellets obtained with a nozzle in accordance with theinvention may have a substantial spherical shape with an aspect ratioclose to 1, preferably ranging from 0.8 to 1. According to one example,the liquid feeding device of the present invention can be used for theproduction of essentially or predominantly spherical freeze-driedmicropellets with a mean value for the diameters thereof chosen from arange of about 200 μm to about 1500 μm, or from about 400 μm to about1000 μm, and more preferably from about 500 μm to about 800 μm. Themicropellets obtained with a nozzle according to the invention have anarrow distribution around a mean value. Preferably, they also have asubstantial symmetric or normal distribution around a mean value. Thespan which represents the narrowness of distribution of particles arounda mean value is calculated according to the formula: (D₉₀−D₁₀)/D₅₀ whereD₉₀, D₁₀ and D₅₀ represent, respectively, the diameters of 90% or less,10% or less, and 50% or less of the particles. The micropellets obtainedwith a nozzle in accordance with the invention may have a span equal orbelow about 1, preferably equal or below about 0.8, further preferablyequal or below about 0.7, further preferably equal or below about 0.6,further preferably equal or below about 0.4, and even further preferablyequal or below about 0.2. According to one embodiment, when using anozzle in accordance with the invention having a diameter of 300 μm, thespan of the obtained particles may be equal or below about 0.8,preferably equal or below about 0.7, and more preferably equal or belowabout 0.6. The measure of the size of micropellets obtained with anozzle in accordance with the invention may be made by lasergranulometry (or laser-diffraction scattering) using, for example, aMalvern Mastersizer 2000 apparatus. For example, a sample ofmicropellets (e.g. of a volume of 50 ml) may be prepared under nitrogenflushing. The sampler used may be a SCIROCCO 2000a with a large hopper.The measure is performed using the Fraunhofer method, with a measure ofthe background noise for 10 seconds, a measuring time of 60 seconds,pressure of 0.8 bar, vibration at 50% and obscuration between 0.5% and40%.

The term “bulkware” can be broadly understood as referring to a systemor plurality of particles which contact each other, i.e., the systemcomprises multiple particles, microparticles, pellets, and/ormicropellets. For example, the term “bulkware” may refer to a looseamount of pellets constituting at least a part of a product flow, suchas a batch of a product to be processed in a process device or a processline, wherein the bulkware is loose in the sense that it is not filledin vials, containers, or other recipients for carrying or conveying theparticles/pellets within the process device or process line. Similarholds for use of the substantive or adjective “bulk.” The bulkware asreferred to herein will normally refer to a quantity of particles(pellets, etc.) exceeding a (secondary, or final) packaging or doseintended for a single patient. Instead, the quantity of bulkware mayrelate to a primary packaging; for example, a production run maycomprise production of bulkware sufficient to fill one or moreintermediate bulk containers, so called IBCs.

Flowable materials suitable for the liquid feeding device of the presentinvention include liquids and/or pastes which, for example, have aviscosity of less than about 300 mP*s. As used herein, the term“flowable materials” is interchangeable with the term “liquids” for thepurpose of describing materials being fed by the present liquid feedingdevice to the subsequent devices or sections. Any material may besuitable for use with the techniques according to the invention in casethe material is flowable, and can be atomized and/or prilled. Further,the material must be congealable and/or freezable.

The terms “sterility” or “sterile conditions” and “containment” or“contained conditions” are understood as required by the applicableregulatory requirement for a specific case. For example, “sterility”and/or “containment” may be understood as defined according to GMPrequirements.

Embodiments of the liquid feeding device may comprise any device adaptedfor a droplet generation from a liquid as described above. Freezing canbe achieved by gravity fall-down of the droplets in a chamber, tower, ortunnel. Exemplary freezing chambers include, but are not limited toprilling chambers or towers, atomization devices such as atomizationchambers, nebulization/atomization and freezing equipment, etc.

In particular embodiments, the entire liquid feeding device (or sectionsthereof) can be adapted for CiP and/or SiP. Access points forintroduction of a cleaning medium and/or a sterilization medium,including, but not limited to use of nozzles, steam access points, etc.,can be provided throughout the sections of the device. For example,steam access points can be provided for steam-based SiP. In some ofthese embodiments, all or some of the access points are connected to onecleaning and/or sterilization medium repository/generator. For example,in one variant, all steam access points are connected to one or moresteam generator in any combination.

Various embodiments of the present invention provide one or more of theadvantages discussed hereafter. For example, with the liquid feedingdevice as presented herein, it is possible to avoid all disadvantages ofthe known prior art. In particular, with the liquid feed device of thepresent invention, it becomes possible to achieve the desired productquality like particle size and particle size distribution in a veryearly stage of the production process.

Furthermore, with the stainless steel membrane of the presented liquidfeeding device, receiving an FDA certificate may be facilitated comparedto the known PTFE membranes or the like.

Moreover, mounting of the inner structure of the liquid feeding deviceis simplified, wherein it becomes possible to remove the magnet withoutdifficulty compared to the known prior art in which the head of thenozzle with fixing of the electromagnetic coil has to be screwedtogether with the membrane flange and the nozzle body, such that aremoval of the magnet during sterilization becomes impossible (heatingreduces the permanent magnetic properties). Also, since the magnet asprovided in the devices as known from the above cited prior art is gluedto the membrane, fixing of the magnet on the membrane is weak such that,during disassembling and cleaning, the magnet it is often separated fromthe membrane and has to be glued again onto the membrane; also, aseparation of the magnet from the membrane is facilitated by hotsurfaces, which will be the case during sterilization. The thus heatsensitive magnet, however, needs to be in position all the time.

As a further advantage of the present invention, deaeration of thenozzle is possible with the structure of the liquid feeding device ofthe present invention, which is necessary for a clear droplet formation.

Also, it has not been possible with the known drilled nozzles of theprior art to achieve straight vertical droplet jets. All known stainlesssteel nozzle tips directly processed into a stainless steel nozzle mainbody showed an undesired tilted liquid droplet jet. Only by providingthe nozzle body separate from the main body during drilling and fixatingthe same into the main body afterwards, an improved nozzle channel hasbeen generated which results in an improved straight droplet jet.

Furthermore, with a liquid feeding device as presented herein, inparticular by providing the liquid chamber with an outlet port, itbecomes possible to achieve sufficient steam throughput forsterilization, and thus, it becomes possible to equip a process line forthe production of freeze-dried particles with the possibility tomaintain closed conditions at all times, even during sterilizationprocedures. Therefore, sterile and/or contained product handling isenabled while avoiding the necessity of putting the entire process lineinto a separator or isolator. In other words, a process line providedwith a liquid feeding device according to the invention adapted forexample for an operation under sterile conditions can be operated in anunsterile environment. Costs and complexity related to using an isolatorcan therefore be avoided while still conforming to sterile and/orcontainment requirements, for example GMP requirements. For example,there may be an analytical requirement of testing in regular timeintervals (e.g., every hour or every few hours) whether sterileconditions are still maintained inside an isolator. By avoiding suchcostly requirements, production costs can be considerably reduced.

The liquid feeding device according to the invention is applicable forfeeding droplets into different kinds of process lines for production ofmany formulations and/or compositions suitable for freeze-drying. Thismay include, for example, generally any hydrolysis-sensitive material.Suitable liquid formulations include, but are not limited to, antigens,adjuvants, vaccines, antibodies (e.g., monoclonal), antibody portionsand fragments, other protein-based Active Pharmaceutical Ingredients(APIs) (e.g., DNA-based APIs, and cell/tissue substances), APIs for oralsolid dosage forms (e.g., APIs with low solubility/bioavailability),fast dispersible or fast dissolving oral solid dosage forms (e.g., ODTs,orally dispersible tablets), and stick filled presentations, etc.

Also, with the deflection section for separating the droplets from eachother by means of at least one gas jet of the liquid feeding device,some disadvantages which may occur further to the droplet separation byelectrostatic charge of the droplets or the like may be avoided, such asthe undesired sticking of the charged droplets to surfaces of afreeze-dryer.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Further aspects and advantages of the invention will become apparentfrom the following description of particular embodiments illustrated inthe figures in which:

FIG. 1 is a schematic illustration of a product flow in a process linecomprising a liquid feeding device according to a preferred embodimentof the invention;

FIG. 2 is a schematic illustration of a configurational mode of theprocess line as illustrated on FIG. 1;

FIG. 3 shows an overall structure of a process line as illustrated inFIGS. 1 and 2;

FIG. 4 shows a side view of the liquid feeding device according to thepreferred embodiment of the invention;

FIG. 5 is a cross-sectional view of the liquid feeding device of FIG. 4along line A-A;

FIG. 6 is a cross-sectional view of the liquid feeding device of FIGS. 4and 5 along line B-B in FIG. 5;

FIG. 7a is an enlarged view of detail “X” in FIG. 5;

FIG. 7b is an enlarged view of detail “Y” in FIG. 6, illustrating onedeflection tube of the liquid feeding device according to the preferredembodiment of the invention in cross-section;

FIG. 8 is an enlarged view of the respective parts of an alternativestructure of the actuation portion of the liquid feeding deviceaccording to the preferred embodiment of the invention, and

FIG. 9 is an enlarged view of a deflection section of a liquid feedingdevice according to another preferred embodiment of the invention incross-section.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

As a general overview, FIG. 1 schematically illustrates a process line100 for the production of freeze-dried particles in the form of pellets,wherein a product flow 102 is assumed to pass through the process line100 under closed conditions 104, also referred to as enclosure 104. Aliquid feeding device 200 in accordance with a preferred embodiment ofthe present invention feeds liquid to a freezing chamber 300, also knownas prilling chamber or prilling tower, in the form of ejected droplets(see also droplets 103 in FIG. 3), where the liquid is subjected tofreeze-congealing. Prilling is a method of producing reasonably uniformspherical particles from liquid solutions. It essentially consists oftwo operations, firstly producing liquid droplets and secondlysolidifying them individually by cooling. The prilling technology isalso known as “laminar jet break-up” technology. The resulting frozendroplets are then transferred via a first transfer section 400 to afreeze-dryer 500 in which the frozen droplets are lyophilized. Afterlyophilization, the thus produced pellets are transferred via a secondtransfer section 600 to a discharge station 700, which provides for afilling of the pellets under closed conditions into final recipients106, typically in the form of IBCs (“Intermediate Bulk Containers”)which are then removed from the process line 100.

Enclosure 104 is intended to indicate that the product flow 102 fromentry to exit of process line 100 is performed under closed conditions,i.e., the product is kept under sterility and/or containment. Theprocess line provides closed conditions without the use of an isolator,the role of which is indicated by dashed line 108 which separates line102 from environment 110. Instead of the need of an isolator, enclosure104 separates product flow 102 from the surrounding environment 110,wherein enclosure 104 is implemented individually for each of thedevices 200, 300, 500, 700 and transfer sections 400, 600 of processline 100. Thus, the object of end-to-end protection of sterility and/orcontainment of the product flow 102 in the entire process line 100 isachieved without putting the entire process within one single device,such as an isolator as known from prior art. Instead, the process line100 according to the invention comprises separate process devices, e.g.,one or more prilling tower, freeze-dryer, discharge station, etc., whichare connected as indicated in FIG. 1 by one or more transfer sections400, 600 to form an integrated process line 100 enabling aninterface-free end-to-end (or start-to-end) product flow 102.

In an alternative view, FIG. 2 schematically illustrates theconfiguration of the process line 100 for the production of freeze-driedparticles under closed conditions as shown in FIG. 1. Briefly, theproduct is flowing as indicated by arrow 102 and is preferably keptsterile and/or contained by accordingly operating each of the separatedevices including liquid feeding device 200, freezing chamber 300,freeze-dryer 500 and first transfer section 400 under sterileconditions/containment, which is intended to be indicated by therespective enclosure parts 1042, 1043, 1045, and 1044 of enclosure 104.The discharge station 700, while not currently under operation in theshown state of process line 100, is also adapted for protectingsterility/providing containment by enclosure part 1047, and the secondtransfer section 600, while currently separating the devices 200, 300,500 from the discharge station 700 in the shown state of process line100, is also adapted for protecting sterility/providing containment byenclosure part 1046. Thus, in the exemplary configuration of the processline 100 as illustrated in FIG. 2, the first transfer section 400 isconfigured in an open state not to limit or interfere with the productflow 102, while the second transfer section 600 is configured tosealably separate the freeze-dryer 500 and discharge station 700, i.e.,the second transfer section 600 operates to seal the freeze-dryer 500and provide closed conditions 1046, 1047 in this respect.

Each of the devices 200, 300, 500, 700 and the transfer sections 400,600 are separately adapted and optimized for operation under closedconditions, wherein “operation” refers to at least one mode of operationincluding, but not limited to, production of freeze-dried particles, ormaintenance modes. Here, a sterilization of a process device or transfersection naturally also requires that the device/section is adapted tomaintain sterility/containment. For example, as symbolized by CiP/SiPsystem 105 in FIG. 2, cleaning and/or sterilization of a process deviceor transfer section may not require any mechanical or manualintervention in that it is performed automatically in place throughoutthe process line 100 or in parts thereof. Automatic control ofrespective valves or similar separating means provided in associationwith the transfer sections, preferably by remote access thereto, alsocontribute to configurability of the process line 100 for differentoperational configurations without mechanical and/or manualintervention.

The details of how process devices such as freezing chambers orfreeze-dryers can protect sterility and/or provide containment for theproducts processed therein depend on the specific application. Forexample, the sterility of a product is protected or maintained bysterilizing the involved process devices and transfer sections. It is tobe noted that—after a sterilization process—a process volume confinedwithin a hermetically closed wall will be considered sterile during agiven time under particular processing conditions, such as, but notlimited to, processing of the product under slight excess (positive)pressure compared to an environment 110. Containment can be consideredto be achieved by processing the product under slightly lowered pressurecompared to the environment 110. These and other appropriate processingconditions are known to the skilled person. As a general remark,transfer sections such as transfer sections 400, 600 depicted in FIGS. 1and 2 have to ensure that product flow 102 through them is accomplishedunder closed conditions; this includes the aspect that closed conditionshave to be ensured/maintained also for a transition of product into andout of the respective transfer section. In other words, an attachment ormounting of a transfer section to a device for achieving a producttransfer has to preserve the desired closed conditions.

FIG. 3 illustrates a process line 100 as basically known from, forexample, EP 2 578 974 A1, following the principles as described inregard to FIGS. 1 and 2. The process line 100 as shown in FIG. 3 isdesigned for the production of freeze-dried pellets under closedconditions, and is adapted to apply the liquid feeding device 200according to the preferred embodiment of the present invention. Theprocess line 100 substantially comprises a prilling tower as a specificembodiment of a freezing chamber 300, a freeze-dryer 500, and adischarge station 700. Here, the freezing chamber 300 and thefreeze-dryer 500 are permanently connected to each other via a firsttransfer section 400, while the freeze-dryer 500 and the dischargestation 700 are permanently connected to each other via a secondtransfer section 600. Each transfer section 400, 600 provides forproduct transfers between the connected process devices.

The liquid feeding device 200 indicated only schematically in FIG. 3 isfor providing the liquid product along the product flow 102 to thefreezing chamber 300. Droplet generation by the liquid feeding device200 into the freezing chamber 300 is affected by flow rate, viscosity ata given temperature, and further physical properties of the liquid to beejected, as well as by the processing conditions of the atomizingprocess, such as the physical conditions of the spraying equipmentincluding frequency, pressure, etc. Therefore the liquid feeding device200 is adapted to controllably deliver the liquid and to generallydeliver the liquid in a regular and stable flow. To this end, the liquidfeeding device 200 can be connected to one or more liquid pumps. Anypump may be employed which enables precise dosing or metering. Examplesfor appropriate pumps may include, but are not limited to, peristalticpumps, membrane pumps, piston-type pumps, eccentric pumps, cavity pumps,progressive cavity pumps, Mohno pumps, etc. Such pumps may be providedseparately and/or as part of control devices such as pressure dampingdevices, which can be provided for an even flow and pressure at theentry point into the liquid feeding device 200. Alternatively oradditionally, the liquid feeding device 200 may be connected to atemperature control device, for example a heat exchanger, for coolingthe liquid in order to reduce the freezing capacities required withinthe freezing chamber 300. The temperature control device may be employedto control the viscosity of the liquid and in turn, in combination withthe feed rate, influence the droplet size and/or droplet formation rate.The liquid feeding device 200 can have one or more flow meters connectedupstream thereof for sensing the liquid feed rate. One or morefiltration components can also be provided upstream of the liquidfeeding device 200. Examples for such filtration components include, butare not limited to, mesh-filters, fabric filters, membrane filters, andadsorption filters. The liquid feeding device 200 can also be connectedto a means configured to provide for sterility of the liquid to beejected; additionally or alternatively, the liquid can be provided tothe liquid feeding device 200 in presterilized form.

The freezing of the droplets 103 ejected and—thus—fed from the liquidfeeding device 200 to the freezing chamber 300 may be achieved, forexample, such that the diluted composition, i.e., the formulated liquidproduct, is prilled. “Prilling” may be defined as a frequency-inducedbreak-up of a constant liquid droplet ejection jet into discretedroplets 103. Generally, the goal of prilling is to generate calibrateddroplets 103 with diameter ranges for example from about 200 μm to about1500 μm, with a narrow size distribution. For instance, the droplets mayhave a span equal or below about 1, preferably equal or below about 0.8,preferably equal or below about 0.7, preferably equal or below about0.6, preferably equal or below about 0.4. The droplets 103 fall into thefreezing chamber 300 in which a spatial temperature profile might bemaintained with, for example a value of between −40° C. to −60° C.,preferably between −50° C. and −60° C., in a top area and between −150°C. to −192° C., for example between −150° C. and −160° C., in a bottomarea of the chamber 300. Lower temperatures may be reachable by coolingsystems employing helium, for example. The droplets freeze during theirfall in order to form preferably spherical, calibrated frozen particles,i.e. micropellets.

Cooling the inner volume of the freezing chamber 300 sufficiently forfreezing the falling droplets 103 can be achieved by means of coolingthe inner wall surface of the chamber 300 via a cooling mediumconducting tubing or the like, and providing the freezing chamber 300with an appropriate height. Therefore, a counter- or concurrent flow ofcooled gas in the chamber's internal volume or other measure for directcooling of falling droplets 103 can preferably be avoided. By avoidingcontact of a circulating primary cooling medium such as a counter- orconcurrent flow of gas with the falling product 103, the requirement ofproviding a costly sterile cooling medium is avoided when sterileproduction runs are desired. The cooling medium circulating outside thechamber's inner volume, for example in tubing or the like, need not tobe sterile. A cooling medium may be, for example, liquid nitrogen. Inone embodiment, the freezing chamber 300 may comprise—with regard to thedirection of the droplet flow—a counter-current flow or a concurrentflow of a cooling medium. In another embodiment, the freezing chamber300 may be devoid of any counter-current or concurrent flow of coolingmedium. In such a case, the congealing or freezing of the droplets isensured by the cooling of the inner wall of the chamber. The droplets103 are frozen on their gravity-induced fall within the freezing chamber300 due to cooling mediated by the temperature-controlled wall chamber300 and an appropriate non-circulating atmosphere provided within theinternal volume, for example, an (optionally sterile) nitrogen and/orair atmosphere.

As an example, in the absence of further cooling mechanisms, forfreezing droplets 103 into substantially spherical micropellets withdiameters in the range of 200-800 μm, an appropriate height of theprilling tower might be 1-2 m, while for freezing droplets into pelletswith a size range up to 1500 μm, the prilling tower can have a height ofabout 2-3 m, wherein the diameter of the prilling tower can be betweenabout 50-150 cm for a height of 200-300 cm. The temperatures in theprilling tower can optionally be maintained or varied/cycled throughoutbetween about −50° C. to −190° C.

The frozen droplets 103 reaching the bottom of the chamber 300 are thenautomatically transferred by gravity towards and into the first transfersection 400, from where the frozen droplets 103 are transferred into arotary drum 501 of the freeze-dryer 500, in which sublimation of thefrozen droplets 103 results in freeze-dried pellets under vacuumconditions generated by a vacuum pump for providing a vacuum in theinternal volume of the freeze-dryer 500 and, thus, the internal volumeof the drum 501. Afterwards, the freeze-dried pellets are transferredvia the second transfer section 600 into the discharging station 700, inwhich the freeze-dried pellets are filled into vials 701 for shipping.

FIG. 4 shows the liquid feeding device 200 according to the preferredembodiment of the invention, which liquid feeding device 200 comprises adroplet ejection section 210 with an actuation portion 220 and a nozzleportion 230, a CiP/SiP section 240, a droplet counting section 250 and adeflection section 260, in this order from top to bottom of the drawing.The order of the sections of the liquid feeding device 200 from top tobottom, i.e. from section 210 to section 260 coincides with thedirection of product flow inside the liquid feeding device 200. Ingeneral, the actuation portion 220 of the droplet ejection section 210serves for generating magnetic waves by alternating positive andnegative magnetizations of a coil, which waves are used for effectingmagnetic impulses resulting in an ejection of droplets from the nozzleportion 230 of the droplet ejection section 210. Here, an outlet port235 of the nozzle portion 230 can also be gathered from FIG. 4, whichoutlet port 235 will be described later in further detail.

The subsequently arranged CiP/SiP section 240 serves for cleaning and/orsterilizing the interior of the liquid feeding device 200, preferably byintroducing steam into the liquid feeding device 200, thereby achievingsteam pressure sterilization of the parts of the interior of the liquidfeeding device 200 penetrable by the steam. Here, the steam can beintroduced by inlet 241 into the CiP/SiP section 200 from the outside,wherein the inlet 241 can be connected to any kind of fluid deliveringmeans, such as a steam pressure pump or the like for SiP procedures, orto a cleaning fluid pump or the like for CiP procedures. The dropletcounting section 250 following the CiP/SiP section 240 serves forcounting the generated droplets, wherein the CiP/SiP section 240requires a predetermined length in order to provide sufficienttravelling distance, such as 30 mm to 50 mm, for the ejected liquid jetto separate in an ejection direction into separate droplets.

The droplet counting section 250 utilizes an optical device foroptically registering the droplets passing through, such as a glasscylinder comprising light emitting optical fibers and light receivingoptical fibers arranged opposite to each other across the area throughwhich the droplets pass. Finally, the liquid feeding device 200 of thepreferred embodiment comprises a deflection section 260 arrangedsubsequently to the droplet counting section 250, the deflection section260 employing at least one gas jet 261 directed towards the dropletejection path 211, wherein the gas jet 261 is discharged by deflectiontubes 262, 263. The droplet counting section 250 can also be positionedat another location along the travel path of the droplets, as long asthe necessary travelling distance of 30 to 50 mm required for the liquidjet to separate into droplets is maintained. The fluid for generatingthe gas jet 261 is introduced into the deflection section 260 and, thus,into the deflection tubes 262, 263 through a deflection gas inlet 267which can be connected to any kind of gas delivering means, such as agas pump or the like. The introduced gas can be air or alternatively anyinert gas, such as any one of Nitrogen, Helium, Argon or Xenon, or thelike. Here, a droplet ejection path 211 (see FIG. 7a ) basicallycoincides with the longitudinal axis 201 of the liquid feeding device200. In general, the CiP/SiP section 240, the droplet counting section250 and the deflection section 260 each comprises a respective recesspassing therethrough, wherein these recesses are connected with eachother such that the droplets ejected from the droplet ejection section210 can pass through the sections 240, 250 and 260 in order to exit theliquid feeding device 200 at its lower end, passing by the deflectiontubes 262, 263 such that the droplets interact with the gas jet 261.

The mounting of the entire liquid feeding device 200 needs to ensurethat all of its sections 210, 240, 250 and 260 are in verticalalignment, in particular in order to achieve the intersection of theejected droplets, i.e. the droplet ejection path with the at least onedeflection gas jet 261. In practice, the different sections can beattached to each other by known means such as clamping components,screws or the like, and the transition areas between the differentsections can be provided with known sealing elements, such as O-Rings orthe like, in order to maintain closed conditions. The alignment of thedifferent sections to each other can be achieved for example by knowncentering means, such as a combination of centering bores and respectivecentering protrusions at the transition areas of the single sections. Inorder to reduce the technical detail of the drawings, these knowncomponents (O-rings, screws, centering protrusions, etc.) have beenomitted in the drawings for the sake of a clearer overview.

FIG. 5 shows a cross-section of the liquid feeding device 200 along theline A-A in FIG. 4. Here, it can be gathered that the actuation portion220 consists of an excitation unit 221 and a main body 222 consisting ofantimagnetic material, such as plastic material (PTFE, i.e. Teflon, orthe like), Aluminum, non-magnetic stainless steel or the like, whereinthe excitation unit 221 basically consists of an electromagnetic coil223 and a coil core arranged there inside, such as an iron core or thelike. The combination of electromagnetic coil 223 and coil core act as asimple electromagnet for applying a magnetic force to a magnetic forcereceiving member, here in the form of a membrane 234 of the nozzleportion 230. The detailed structure of the nozzle portion 230 of thedroplet ejection section 210 can be gathered from FIG. 7a , in which thedetail “X” as indicated in FIG. 5 is shown in an enlarged view. FromFIG. 7a , it can be gathered that the nozzle portion 230 comprises aninlet port 231, a liquid chamber 232 having a cross axis or lateral axis2321 and a longitudinal axis 2322 and being arranged in an inclinedmanner, a nozzle 233 through which the liquid from the liquid chamber232 is ejected, the mentioned membrane 234 constituting one side of theliquid chamber 232, the outlet port 235, also referred to as bypass orbypass port, and a main body 236 of the nozzle portion 230, in which theinlet port 231, the liquid chamber 232, the nozzle 233, the membrane 234and the outlet port 235 are accommodated. Furthermore, the nozzle 233 isprovided in a nozzle body 237 for manufacturing reasons, such that anozzle orifice 2331 opens into a central through-hole provided in theCiP/SiP section 240, and the nozzle orifice 2331 is connected to theliquid chamber by a nozzle channel 2332. The nozzle 233 comprises alongitudinal axis 2333 proceeding coaxially to the droplet ejection path211 and to the longitudinal axis 201 of the liquid feeding device 200.Here, the liquid chamber 232 is arranged in an inclined manner such thatits longitudinal axis 2322 is tilted in regard to the longitudinal axis2333 of the nozzle 233, preferably with an extend of 2-5°, furtherpreferably 3°. The nozzle body 237 is permanently installed/inbuilt in acentral through-hole 2361 provided in the main body 236, wherein thenozzle body can be attached to the main body 236 by laser-welding or thelike.

In FIG. 8, a further development of the actuation portion 220 can begathered, which is applicable to the liquid infeed device 200 of thepreferred embodiment. In the further developed actuation portion 220,the excitation unit 221 comprises a combination of a cylindricallyshaped permanent magnet 224 separably attachable to the membrane 234opposite the liquid chamber 232 and the above mentioned combination ofelectromagnetic coil 223 and coil core acting as a simple electromagnet.A damping element 225 in the form of an inverted U-shape, i.e. in theform of an inverted cup-shape, is provided around the permanent magnet224 with its cup-bottom between the magnet 224 and the coil-coil corecombination for achieving a damping effect between the magnet 224 andthe coil 223, wherein the damping element 225 can be made out ofsilicone. The damping element 225 is provided basically in a cup-shapedmanner in a way that the electromagnetic coil 223 and the magnet 224 allhave defined positions in relation to each other. The damping element225, also referred to as damper, can increase the displacement of themagnet 224, the damping element 225 covering the transversalcircumference of the magnet 224, thereby arranging the magnet 224 insidethe inner recess of the damping element 225 in a way that the magnet 224can be just mounted centrically in regard to the damping element 225and, thus, in regard to the electromagnetic coil 223, to avoid anytilting of the magnet 224 or its contact with the coil 223 or the coilcore, resulting in the desired damping effect.

The inlet port 231 opens into the liquid chamber 232 near theintersection between liquid chamber 232 and nozzle channel 2332. Theoutlet port 235 opens into the liquid chamber 232 at an outercircumference of the liquid chamber 232 at the highest possible positiondue to the tilting of the liquid chamber 232, such that liquid in theliquid chamber 232 may only exit the liquid chamber 232 through theoutlet port 235 in case the liquid chamber 232 is entirely filled withliquid and the outlet port 235 enables a drainage of the liquid. Theinlet port 231 can be connected to a liquid source, such as apressurized liquid tank, a peristaltic pump or the like, wherein apressurized liquid tank is a preferred option since no pressurefluctuations of the infed liquid occur due to the constant pressureinside the tank, wherein a peristaltic pump can exhibit pressurefluctuations of the infed liquid. The outlet port 235, on the otherhand, can be connected to a drain tank, drain tubing, a liquidcollection container or the like, wherein a blocking means can beprovided subsequently to the outlet port 231, such as a check valve, ashut-off valve or the like. During droplet generation, i.e. dropletejection into the freezing chamber 300, the liquid transferred throughthe liquid inlet port 231 into the liquid chamber 232 is the liquid tobe ejected, such as, for example, antigens, adjuvants, vaccines,antibodies, APIs, ODTs, blood plasma components, or the like. However,since it is not or only insufficiently possible to provide CiP/SiP fluidfrom the CiP/SiP section 240 into the liquid chamber 232 through thenozzle orifice 2331 due to its minute inner diameter, the inlet port 231can also be used to provide such CiP/SiP fluid through the inlet port231 into the liquid chamber 232 and out of the outlet port 235, whereinthe large diameters of the ports 231, 235 (large compared to thediameter of the nozzle orifice 2331) allow a substantial CiP/SiP fluidflow volume, resulting in excellent CiP/SiP results of the dropletejection section 210 without the need of disassembling the liquidfeeding device 200. Here, as an example of dimensions, the diameter ofthe liquid inlet port 231 can reside in a range of 0.9 mm to 1.3 mm,preferably 1.1 mm, and the diameter of the outlet port 235 can reside ina range of 0.8 mm to 1.2 mm, preferably 1.0 mm. Compared to an exemplarydiameter of the nozzle orifice 2331 of about 300 μm, this results in adiameter ratio port/orifice of about 3:1 to 4:1.

As can also be gathered from FIG. 7a in detail, besides the inlet 241,the CiP/SiP section 240 consists of a main body 242 sandwiched betweenthe nozzle portion main body 236 as well as a main body 264 of thedeflection section 260. In the CiP/SiP section main body 242, a centralthrough-hole 243 as a transition zone for the droplets is provided as astraight bore hole in a cylindrical form. Furthermore, a fluid chamber244 is provided in the main body 242, which fluid chamber 244 isarranged circumferentially around the through-hole 243, wherein thefluid chamber 244 is connected to the inside of the through-hole 243 byseveral fluid channels 245 for providing the CiP/SiP fluid coming fromthe inlet 241 into the through-hole 243 of the CiP/SiP section 240 and,thus, into the sections connected to the CiP/SiP section 240, such asthe droplet counting section 250 and the deflection section 260. Thefluid channels 245 are preferably provided in an inclined manner suchthat they open into the through-hole 243 with an angle, therebyproviding any CiP/SiP fluid streamed into the through-hole 243 with aspin, resulting in an improved cleanability/sterilizability effect ofthe CiP/SiP section 240 and, thus, the other sections of the liquidfeeding device 200 fluid-connected to the CiP/SiP section 240. Also, inaddition, the inclined fluid channels 245 can be used to inject gas withthe purpose of interfering with the ejected droplets on their ejectionpath 211 such that the separation of the droplets can be furtherpromoted.

In the direction of the droplet path 211, subsequently to the CiP/SiPsection 240, the droplet counting section 250 is arranged, wherein thedroplet counting section 250 comprises a main body 251 and an opticalcounting component 252. Here, the optical counting component 252 can besandwiched between two parts of the main body 251 for the sake ofsimplified installation. The optical counting component 252 of thepreferred embodiment can be a see-through glass tube with ports forfibre optics (not shown in detail), wherein the fibre optics serve forcounting the droplets by means of an optical sender and an opticalreceiver, in between of which the ejected droplets pass through. Inparticular, the glass tube can be introduced as a glass cylinderintegrated into a flange that carries opening ports to take up a lightemitting sender and a respective receiver for registering the dropletspassing through, the flange being sandwiched between the mentioned partsof the main body 251.

As a further part of the liquid feeding device 200 which can be gatheredfrom FIGS. 5 and 6, the deflection section 260 follows the dropletcounting section 250 in an ejection direction 212 of the liquid and,thus, of the ejected droplets, wherein the deflection section 260 servesfor spreading the droplets, i.e. separating the droplets from each otherby means of the at least one gas jet 261 in order to avoid coalescenceof the droplets prior to freezing and to improve the heat transfer. Theat least one gas jet 261 of the deflection section 260 is provided bytwo deflection tubes, deflection tube 262 and deflection tube 263, whichare arranged directly opposite to each other, with the droplet ejectionpath 211 proceeding in between. As already mentioned above, the fluidfor generating the gas jet 261 is introduced into the deflection section260 through a main body 264 and, thus, into the deflection tubes 262,263 through the deflection gas inlet 266 which can be connected to anykind of gas delivering means, such as a gas pump or the like. The gasjet 261 is directed towards the droplet ejection path 211 such that thegas jet 261 or better the several gas jets 261 of the preferredembodiment impact on the ejected droplets on the ejection path 2111 witha right angle.

Therefore, as can be gathered from FIG. 7b in detail, each deflectiontube 262, 263 is hollow and comprises several gas jet outlet ports, i.e.the deflection tube 262 comprises three gas jet outlet ports 2621, 2622,2623, and the deflection tube 263 comprises three gas jet outlet ports2631, 2632, 2633. The outlet ports 2621, 2622, 2623 connect the hollowinterior of tube 262 with the outside, and the outlet ports 2631, 2632,2633 connect the hollow interior of tube 263 with the outside, i.e. withthe interior of the freezing chamber 300. Here, the uppermost gas jetoutlet port 2631 of deflection tube 263 is arranged directly opposite tothe uppermost gas jet outlet port 2621 of deflection tube 262, themiddle gas jet outlet port 2633 of deflection tube 263 is arrangeddirectly opposite to the middle gas jet outlet port 2623 of deflectiontube 262, and the lowest gas jet outlet port 2632 of deflection tube 263is arranged directly opposite to the lowest gas jet outlet port 2622 ofdeflection tube 262, in an order from top to bottom in the ejectiondirection 212. The lowest gas jet outlet port 2622, 2632 of eachdeflection tube 262, 263 is arranged at its tip and connects with arespective interior of each tube 262, 263 at its edge, such that eachdeflection tube 262, 263 is self-draining, meaning that any fluid ineach tube 262, 263 is drained therefrom through the respective lowestgas jet outlet port 2622, 2632 by means of gravity. In order to providethe gas jet fluid to the deflection tubes 262, 263, the hollow interiorof each tube 262, 263 is fluid-connected with a fluid chamber 266provided in the main body 264, which fluid chamber 266 is connected tothe gas inlet 266 and is arranged circumferentially around a centralthrough-hole 265 provided in the main body 264 for letting the dropletspass through the deflection section's main body 264.

According to the preferred embodiment of the liquid feeding device 200of the present invention, the main body 264 is an integral component.However, in accordance with a further embodiment, the main body 264 canalso consist of several parts being mechanically connected, for examplein the form of a clamping means, screws or the like, wherein the insideof the main body 264, i.e. the inside of the fluid chamber 266 needs tobe fluid-tightly closed against the outside, for example by means of asealing component such as an O-ring, a gasket or the like. Moreover,according to the preferred embodiment of the liquid feeding device 200of the present invention, the central through-hole 265 as a transitionzone for the droplets is provided in the form of a straight bore holecentrally extending throughout the main body 264 in a cylindrical form.However, in accordance with a further embodiment, the centralthrough-hole 265 can also exhibit a conical shape, with an increasingdiameter in the ejection 212 towards the deflection tubes 262, 263.Here, the opening of the diameter of the conical shape is preferablychosen to avoid any deposition of small droplets, so called satellites,in the area of the central through-hole.

FIG. 9 shows a modification of the deflection section of the liquidfeeding device according to the above described preferred embodiment ofthe invention, i.e. another preferred embodiment of the invention. Inorder to avoid redundancy, some of the components provided identical tothe above described preferred embodiment are not shown or furtherdescribed but are to be understood as having the same technicalstructure and functionality. Contrary to the above described embodimentof the liquid feeding device 200, the deflection section 260′ of theshown embodiment of the modified liquid feeding device 200′ comprisesfour deflection tubes, i.e. deflection tube 262′, deflection tube 263′,deflection tube 268 and a further deflection tube (not shown) instead ofthe two deflection tubes 262, 263 of the above described embodiment. Dueto the cross-sectional view in FIG. 9, only three of the four deflectiontubes of the present embodiment are shown in FIG. 9, i.e. deflectiontubes 262′, 263′ and 268, whereas the fourth deflection tube is notshown. Similar to the above described deflection section 260, thedeflection section 260′ is arranged subsequently to a droplet countingsection of the liquid feeding device 200′, and the deflection section260′ employs at least four gas jets generated from the four deflectiontubes, which jets are directed towards a droplet ejection path. Thefluid for generating the gas jets is introduced into the deflectionsection 260′ and, thus, into the deflection tubes through a deflectiongas inlet 267′ which can be connected to any kind of gas deliveringmeans, such as a gas pump or the like, which provides the introduced gassuch as air or alternatively any inert gas, such as any one of Nitrogen,Helium, Argon or Xenon, or the like. Similarly to the deflection section260, the deflection section 260′ serves for spreading the droplets, i.e.separating the droplets from each other by means of the at least one gasjet in order to avoid coalescence of the droplets prior to freezing andto improve the heat transfer. The four gas jets of the deflectionsection 260′ are provided by the four deflection tubes, whereindeflection tube 262′ and deflection tube 263′ are arranged directlyopposite to each other, and wherein deflection tube 268 and the furtherdeflection tube (not shown) are arranged directly opposite to eachother, with the droplet ejection path proceeding in between at the crosssection of the gas jets produced by the four deflection tubes. The fluidfor generating the gas jets is introduced into the deflection section260′ through a main body 264′ and, thus, into the deflection tubesthrough the deflection gas inlet 266′ which is connected to thedeflection gas inlet 267′.

The gas jets are directed towards the droplet ejection path such thatthe gas jets impact on the ejected droplets on the ejection path with aright angle to the longitudinal axis of the ejection section 260′. Inorder to be able to do so, each deflection is hollow and comprises oneor several gas jet outlet ports which connect the hollow interior ofeach tube with the outside, i.e. with an interior of a freezing chamberof the process line. The gas jet outlet ports of each deflection tubecan be provided similarly to the above described embodiment, i.e. with anumber of one or several, e.g. three outlet ports for each deflectiontube, the ports being arranged above each other on the same longitudinalaxis. However, it is considered to be understood that the number of theoutlet ports can be one, two, three, four etc., in each deflection tube,as desired, in order to provide as many gas jets as desired. Also, inthe present embodiment, four deflection tubes are arranged in a way suchthat sets of two deflection tubes are arranged opposite to each other,resulting in a crosswise arrangement in the same plane, i.e. in anequiangular arrangement of 90° between two adjacent tubes. Thereby, therespective gas jets on each level of outlet ports meet each other at thedroplet ejection path in a rectangular manner.

As a modification thereof, only three tubes can also be provided,wherein the tubes are then to be arranged again in an equiangularmanner, i.e. with 120° between two adjacent tubes. Moreover, five ormore tubes could also be provided in an equiangular manner as a furthermodification, if desired. As a further alternative embodiment, it isconceivable that all provided gas jet outlet ports are directed to oneand the same location on the droplet ejection path, thereby gatheringthe deflection force of all provided gas jets on the same spot.

The products resulting from a process line 100 applying a liquid feedingdevice 200 or a liquid feeding device 200′ according to the inventioncan comprise virtually any formulation in liquid or flowable paste statethat is suitable also for conventional (e.g., shelf-type) freeze-dryingprocesses, for example, monoclonal antibodies, protein-based APIs,DNA-based APIs; cell/tissue substances; vaccines; APIs for oral soliddosage forms such as APIs with low solubility/bioavailability; fastdispersible oral solid dosage forms like ODTs, orally dispersibletablets, stick-filled adaptations, etc., as well as various products inthe fine chemicals and food products industries. In general, suitableflowable materials for prilling include compositions that are amenableto the benefits of the freeze-drying process (e.g., increased stabilityonce freeze-dried).

The invention improves the generation of, for example, sterilelyophilized and uniformly calibrated particles, e.g., micropellets, asbulkware. The resulting product can be free-flowing, dust-free andhomogeneous. Such products have good handling properties and can beeasily combined with other components, wherein the components might beincompatible in liquid state or only stable for a short time period andthus otherwise not suitable for conventional freeze-drying.

In order to support a permanently mechanically integrated systemproviding end-to-end sterility and/or containment, additionally, aspecific cleaning concept for the liquid feeding device of the presentinvention is contemplated. In a preferred embodiment, a single steamgenerator, or a similar generator/repository for a cleaning and/orsterilization medium can be provided. The cleaning/sterilization systemof the liquid feeding device of the present invention can be configuredto perform automatic CiP/SiP for different sections of the device or ofthe entire device, which avoids the necessity of complex andtime-consuming cleaning/sterilization processes requiring a disassemblyof the liquid feeding device and/or which have to be performed at leastin part manually.

The products resulting from the use of the liquid feeding deviceaccording to the invention can comprise virtually any formulation inliquid or flowable paste state that is suitable also for conventional(e.g., shelf-type) freeze-drying processes, for example, monoclonalantibodies, protein-based APIs, DNA-based APIs, cell/tissue substances,vaccines, APIs for oral solid dosage forms such as APIs with lowsolubility/bioavailability, fast dispersible oral solid dosage formslike ODTs, orally dispersible tablets, stick-filled adaptations, etc.,blood plasma components, as well as various products in the finechemicals and food products industries.

In general, suitable flowable materials for prilling includecompositions that are amenable to the benefits of the freeze-dryingprocess (e.g., increased stability once freeze-dried). The inventionallows the generation of, for example, sterile lyophilized and uniformlycalibrated particles, e.g., micropellets, as bulkware. The resultingproduct can be free-flowing, dust-free and homogeneous. Such productshave good handling properties and can be easily combined with othercomponents, wherein the components might be incompatible in liquid stateor only stable for a short time period and thus otherwise not suitablefor conventional freeze-drying. Freeze-drying in the form of particles,particularly in the form of micropellets allows stabilization of, forexample, a dried vaccine product as known for mere freeze-drying alone,or it can improve stability for storage. The freeze-drying of bulkware(e.g., vaccine or fine chemical micropellets) offers several advantagesin comparison to conventional freeze-drying; for example, but notlimited to, the following: it allows the blending of the dried productsbefore filling, it allows titers to be adjusted before filling, itallows minimizing the interaction(s) between any products, such that theonly product interaction occurs after rehydration, and it allows in manycases an improvement in stability.

In fact, the product to be bulk freeze-dried can result from a liquidcontaining, for example, antigens together with an adjuvant, theseparate drying of the antigens and the adjuvant (in separate productionruns, which can, however, be performed on the same process lineaccording to the invention), followed by blending of the two ingredientsbefore the filling or by a sequential filling. In other words, thestability can be improved by generating separate micropellets ofantigens and adjuvant, for example. The stabilizing formulation can beoptimized independently for each antigen and the adjuvant. Themicropellets of antigens and adjuvant can subsequently be filled intothe final recipients or can be blended before filling into therecipients. The separated solid state allows one to avoid throughoutstorage (even at higher temperature) interactions between antigens andadjuvant. Thus, configurations might be reached, wherein the content ofthe vial can be more stable than any other configurations. Interactionsbetween components can be standardized as they occur only afterrehydration of the dry combination with one or more rehydrating agentssuch as a suitable diluent (e.g., water or buffered saline).

A subject-matter of the invention is relating to a process for preparinga vaccine composition comprising one or more antigens in the form offreeze-dried particles comprising at least a step of generating liquiddroplets of said vaccine composition with a liquid feeding device 200,200′ according to the invention. The obtained droplets are furthersubjected to a step of freeze-drying to obtain freeze-dried particles.The freeze-dried particles may optionally be filled into a recipient.

A subject-matter of the invention is relating to a process for preparinga composition comprising one or more adjuvant(s) in the form offreeze-dried particles comprising at least a step of generating liquiddroplets of said composition with a liquid feeding device 200, 200′according to the invention. The obtained droplets are further subjectedto a step of freeze-drying to obtain freeze-dried particles. Thefreeze-dried particles may optionally be filled into a recipient.

In a further aspect, the invention is relating to a process forpreparing an adjuvant containing vaccine composition comprising one ormore antigens in the form of freeze-dried particles comprising at leasta step of generating liquid droplets of said vaccine composition with aliquid feeding device according to the invention, or at least the stepsof generating liquid droplets of an antigen(s)-containing compositionwith a liquid feeding device according to the invention, of generatingliquid droplets of an adjuvant-containing composition with a liquidfeeding device according to the invention, freeze-drying the droplets toobtain freeze-dried particles, and blending the freeze-dried particlesof antigen(s) with the freeze-dried particles of adjuvant.

Another subject-matter of the invention is relating to a process forpreparing a vaccine composition comprising one or more antigens in theform of freeze-dried particles comprising at least the steps ofgenerating liquid droplets of a liquid bulk solution comprising anadjuvant and one or more antigens with a liquid feeding device accordingto the invention, freeze-drying the obtained droplets, and, optionally,filling the freeze-dried particles obtained into a recipient.

Alternatively when the one or more antigens and the adjuvant are not inthe same solution, the process for preparing an adjuvant containingvaccine composition comprises at least the steps of generating liquiddroplets of a liquid bulk solution comprising an adjuvant, generatingliquid droplets of a liquid bulk solution comprising one or moreantigens, wherein the liquid droplets generated at one of the stepsbefore being generated with a with a liquid feeding device according tothe invention, freeze-drying the obtained liquid droplets to obtainfreeze dried particles of said one or more antigens and freeze driedparticles of said adjuvant, blending the freeze dried particles of saidone or more antigens with the freeze dried particles of said adjuvant,and, optionally, filling the blending of freeze-dried particles into arecipient.

The liquid bulk solution of antigen(s) may contain for instance killed,live attenuated viruses or antigenic component of viruses like Influenzavirus, Rotavirus, Flavivirus (including for instance dengue (DEN)viruses serotypes 1, 2, 3 and 4, Japanese encephalitis (JE) virus,yellow fever (YF) virus and West Nile (WN) virus as well as chimericFlavivirus), Hepatitis A and B virus, Rabies virus. The liquid bulksolutions of antigen(s) may also contain killed, live attenuatedbacteria, or antigenic component of bacteria such as bacterial proteinor polysaccharide antigens (conjugated or non-conjugated), for instancefrom serotype b Haemophilus influenzae, Neisseria meningitidis,Clostridium tetani, Corynebacterium diphtheriae, Bordetella pertussis,Clostridium botulinum, Clostridium difficile. A liquid bulk solutioncomprising one or more antigens means a composition obtained at the endof the antigen production process. The liquid bulk solution ofantigen(s) can be a purified or a non purified antigen solutiondepending on whether the antigen production process comprises apurification step or not. When the liquid bulk solution comprisesseveral antigens, they can originate from the same or from differentspecies of microorganisms. Usually, the liquid bulk solution ofantigen(s) comprises a buffer and/or a stabilizer that can be forinstance a monosaccharide such as mannose, an oligosaccharide such assucrose, lactose, trehalose, maltose, a sugar alcohol such as sorbitol,mannitol or inositol, or a mixture of two or more different of theseaforementioned stabilizers such as a mixture of sucrose and trehalose.Advantageously, the concentration of monosaccharide oligosaccharide,sugar alcohol or mixture thereof in the liquid bulk solution ofantigen(s) ranges from 2% (w/v) to the limit of solubility in theformulated liquid product, more particularly it ranges from 5% (w/v) to40% (w/v), 5% (w/v) to 20% (w/v) or 20% (w/v) to 40% (w/v). Compositionsof liquid bulk solutions of antigen(s) containing such stabilizers aredescribed in particular in WO 2009/109550, the subject-matter of whichis incorporated by reference. When the vaccine composition contains anadjuvant it can be for instance:

1) a particulate adjuvant such as: liposomes and in particular cationicliposomes (e.g. DC-Choi, see e.g. US 2006/0165717, DOTAP, DDAB and1,2-Dialkanoyl-sn-glycero-3-ethylphosphocholin (EthyIPC) liposomes, seeU.S. Pat. No. 7,344,720), lipid or detergent micelles or other lipidparticles (e.g. Iscomatrix from CSL or from Isconova, virosomes andproteocochleates), polymer nanoparticles or microparticles (e.g. PLGAand PLA nano- or microparticles, PCPP particles, Alginate/chitosanparticles) or soluble polymers (e.g. PCPP, chitosan), protein particlessuch as the Neisseria meningitidis proteosomes, mineral gels (standardaluminum adjuvants: AlOOH, A1P04), microparticles or nanoparticles (e.g.Ca3(P04)2), polymer/aluminum nanohybrids (e.g. PMAA-PEG/AlOOH andPMAA-PEG/A1P04 nanoparticles) O/W emulsions (e.g. MF59 from Novartis,AS03 from GlaxoSmithKline Biologicals) and W/O emulsion (e.g. ISA51 andISA720 from Seppic, or as disclosed in WO 2008/009309). For example, asuitable adjuvant emulsion for the process according to the presentinvention is that disclosed in WO 2007/006939;2) a natural extracts such as: the saponin extract QS21 and itssemi-synthetic derivatives such as those developed by Avantogen,bacterial cell wall extracts (e.g. micobacterium cell wall skeletondeveloped by Corixa/GS and micobaterium cord factor and its syntheticderivative, trehalose dimycholate);3) a stimulator of Toll Like Receptors (TLR). It is particular naturalor synthetic TLR agonists (e.g. synthetic lipopeptides that stimulateTLR2/1 or TLR2/6 heterodimers, double stranded RNA that stimulates TLR3,LPS and its derivative MPL that stimulate TLR4, E6020 and RC-529 thatstimulate TLR4, flagellin that stimulates TLR5, single stranded RNA and3M's synthetic imidazoquinolines that stimulate TLR7 and/or TLR8, CpGDNA that stimulates TLR9, natural or synthetic NOD agonists (e.g.Muramyl dipeptides), natural or synthetic RIG agonists (e.g. viralnucleic acids and in particular 3′ phosphate RNA).

When there is no incompatibility between the adjuvant and the liquidbulk solution of antigen(s) it can be added directly to the solution.The liquid bulk solution of antigen(s) and adjuvant may be for instancea liquid bulk solution of an anatoxin adsorbed on an aluminium salt(alun, aluminium phosphate, aluminium hydroxide) containing a stabilizersuch as mannose, an oligosaccharide such as sucrose, lactose, trehalose,maltose, a sugar alcohol such as sorbitol, mannitol or inositol, or amixture thereof. Examples of such compositions are described inparticular in WO 2009/109550, the subject-matter of which isincorporated by reference. The freeze-dried particles of the nonadjuvanted or adjuvanted vaccine composition are usually under the formof spheric particles having a mean diameter between 200 μm and 1500 μm.Furthermore, the freeze-dried particles of the vaccine compositionsobtained are sterile.

While the current invention has been described in relation to itspreferred embodiment, it is to be understood that this description isfor illustrative purposes only. Accordingly, it is intended that theinvention be limited only by the scope of the claims appended hereto.

This application claims priority of European patent application EP 14002 529.7-1351, the subject-matters of which are listed below for thesake of completeness:

Item 1. Liquid feeding device for the generation of droplets, inparticular for the use in a process line for the production offreeze-dried particles, with a droplet ejection section for ejectingliquid droplets in an ejection direction, the droplet ejection sectioncomprising at least one inlet port for receiving a liquid to be ejected,a liquid chamber for retaining the liquid, and a nozzle for ejecting theliquid from the liquid chamber to form droplets, wherein the liquidchamber is restricted by a membrane on one side thereof, the membranebeing vibratable by an excitation unit, wherein the longitudinal axis ofthe liquid chamber is tilted relative to the longitudinal axis of thenozzle, and/or the liquid feeding device further comprises a deflectionsection for separating the droplets from each other by means of a gasjet.

Item 2. Liquid feeding device according to item 1, wherein thedeflection section gas jet intersects with an ejection path of theliquid ejected from the liquid chamber.

Item 3. Liquid feeding device according to item 1 or 2, wherein thedeflection section comprises at least one deflection tube for emittingthe gas jet, the at least one deflection tube protruding from a mainbody of the deflection section in the ejection direction of the liquid.

Item 4. Liquid feeding device according to item 3, wherein thedeflection section comprises two deflection tubes arranged opposite toeach other, and wherein the emitted gas jets meet each other at anejection path of the liquid ejected from the liquid chamber,intersecting with the same.

Item 5. Liquid feeding device according to item 3 or 4, wherein eachdeflection tube comprises at least two gas jet outlet ports, and whereinthe gas jet outlet port at the tip of the respective deflection tubeconnects with the tube interior at its edge, preferably wherein eachdeflection tube comprises three gas jet outlet ports.

Item 6. Liquid feeding device according to any one of the precedingitems, wherein the droplets pass through a recess provided in a mainbody of the deflection section, preferably wherein the recess is acentral through-hole extending through the main body of the deflectionsection.

Item 7. Liquid feeding device according to any one of the precedingitems, wherein the droplet ejection section further comprises at leastone outlet port, preferably wherein the at least one outlet port isarranged at an outer circumference of the liquid chamber.

Item 8. Liquid feeding device according item 7, wherein the longitudinalaxis of the liquid chamber is tilted relative to the longitudinal axisof the nozzle in a way that the at least one outlet port is provided atthe highest level of the liquid chamber.

Item 9. Liquid feeding device according item 7 or 8, wherein the atleast one outlet port serves for drainage of excessive liquid to beejected from the liquid chamber and/or serves for discharge of SiP fluidand/or CiP fluid introduced through the at least one inlet port of thedroplet ejection section.

Item 10. Liquid feeding device according to any one of the precedingitems, wherein the excitation unit comprises a combination of apermanent magnet separably attachable to the membrane opposite theliquid chamber and an electromagnetic coil for actuating the permanentmagnet, preferably wherein a damping element is provided around thepermanent magnet, more preferably also between the permanent magnet andthe electromagnetic coil, further preferably wherein the damping elementis made out of silicone.

Item 11. Liquid feeding device according to any one of the precedingitems, wherein the membrane is a stainless steel membrane.

Item 12. Liquid feeding device according to any one of the precedingitems, wherein the droplet ejection section comprises an actuationportion and a nozzle portion, the actuation portion comprising at leastthe excitation unit, and the nozzle portion comprising at least the atleast one inlet port, the liquid chamber, the nozzle and the membrane.

Item 13. Liquid feeding device according to item 12, wherein the nozzleportion comprises a nozzle portion main body and a nozzle body providedseparately from the nozzle portion main body, preferably wherein thenozzle body is permanently installed in a central through-hole in thenozzle portion main body, more preferably by laser welding.

Item 14. Liquid feeding device according to item 12 or 13, wherein themembrane is welded to the nozzle portion for airtightly closing theliquid chamber on one side, preferably by laser welding.

Item 15. Liquid feeding device according to any one of the precedingitems, further comprising a CiP/SiP section arranged between the dropletejection section and the deflection section, for providing CiP fluidand/or SiP fluid to the parts of the liquid feeding device subsequent tothe droplet ejection section.

Item 16. Liquid feeding device according to any one of the precedingitems, further comprising a droplet counting section for counting thedroplets, preferably provided before the deflection section in theejection direction of the liquid.

Item 17. Freezing chamber of a process line for the production offreeze-dried particles, preferably for the pharmaceutical field,comprising a liquid feeding device according to any one of the precedingitems, for the generation of droplets to be fed into the freezingchamber.

Item 18. Process line for the production of freeze-dried particles,comprising a freezing chamber according to item 17.

Item 19. A process for preparing a vaccine composition comprising one ormore antigens in the form of freeze-dried particles comprising at leasta step of generating liquid droplets of said vaccine composition with aliquid feeding device according to anyone of items 1 to 16.

Item 20. A process for preparing an adjuvant containing vaccinecomposition comprising one or more antigens in the form of freeze-driedparticles comprising:

-   -   at least a step of generating liquid droplets of said vaccine        composition with a liquid feeding device according to anyone of        items 1 to 16, or    -   at least the steps of generating liquid droplets of an        antigen(s)-containing composition with a liquid feeding device        according to anyone of items 1 to 16, of generating liquid        droplets of an adjuvant-containing composition with a liquid        feeding device according to anyone of items 1 to 16,        freeze-drying the droplets to obtain freeze-dried particles, and        blending the freeze-dried particles of antigen(s) with the        freeze-dried particles of adjuvant.

Item 21. A process according to item 19 or 20, wherein all the steps arecarried out under sterile conditions.

Item 22. A process according to items 19 or 21, wherein the freeze-driedparticles are sterile.

What is claimed is:
 1. A liquid feeding device for the generation ofdroplets, for the use in a process line for the production offreeze-dried particles for the pharmaceutical field, with a dropletejection section for ejecting liquid droplets in an ejection direction,the droplet ejection section comprising at least one inlet port forreceiving a liquid to be ejected, a liquid chamber for retaining theliquid, and a nozzle for ejecting the liquid from the liquid chamber toform droplets, wherein the liquid chamber is restricted by a membrane onone side thereof, the membrane being vibratable by an excitation unit,wherein the liquid feeding device further comprises a deflection sectionfor separating the droplets from each other by means of at least one gasjet, and wherein the deflection section gas jet intersects perpendicularwith an ejection path of the liquid ejected from the liquid chamber;wherein the excitation unit is configured to generate a controlledmechanical vibration of the membrane to eject equally sized liquiddroplets from the nozzle.
 2. The liquid feeding device according toclaim 1, wherein the longitudinal axis of the liquid chamber is tiltedrelative to the longitudinal axis of the nozzle and wherein the membraneis a stainless steel membrane.
 3. The liquid feeding device according toclaim 1, wherein the deflection section comprises at least onedeflection tube for emitting the gas jet, the at least one deflectiontube protruding from a main body of the deflection section in theejection direction of the liquid.
 4. The liquid feeding device accordingto claim 3, wherein the deflection section comprises at least twodeflection tubes arranged opposite to each other, and wherein theemitted gas jets meet each other at an ejection path of the liquidejected from the liquid chamber, intersecting with the same.
 5. Theliquid feeding device according to claim 4, wherein the deflectionsection comprises four deflection tubes, and wherein the emitted gasjets meet each other at an ejection path of the liquid ejected from theliquid chamber, intersecting with the same.
 6. The liquid feeding deviceaccording to claim 3, wherein each deflection tube comprises at leasttwo gas jet outlet ports, and wherein the gas jet outlet port at the tipof the respective deflection tube connects with the tube interior at itsedge.
 7. The liquid feeding device according to claim 6, wherein eachdeflection tube comprises three gas jet outlet ports.
 8. The liquidfeeding device according to claim 1, wherein the droplets pass through arecess provided in a main body of the deflection section.
 9. The liquidfeeding device according to claim 8, wherein the recess is a centralthrough-hole extending through the main body of the deflection section.10. The liquid feeding device according to claim 1, wherein the dropletejection section further comprises at least one outlet port.
 11. Theliquid feeding device according claim 10, wherein the longitudinal axisof the liquid chamber is tilted relative to the longitudinal axis of thenozzle in a way that the at least one outlet port is provided at thehighest level of the liquid chamber.
 12. The liquid feeding deviceaccording claim 10, wherein the at least one outlet port serves fordrainage of excessive liquid to be ejected from the liquid chamberand/or serves for discharge of SiP fluid and/or CiP fluid introducedthrough the at least one inlet port of the droplet ejection section. 13.The liquid feeding device according to claim 10, wherein the at leastone outlet port is arranged at an outer circumference of the liquidchamber.
 14. The liquid feeding device according to claim 1, wherein theexcitation unit comprises a combination of a permanent magnet separablyattachable to the membrane opposite the liquid chamber and anelectromagnetic coil for actuating the permanent magnet.
 15. The liquidfeeding device according to claim 14, wherein a damping element isprovided around the permanent magnet.
 16. The liquid feeding deviceaccording to claim 15, wherein the damping element is also providedbetween the permanent magnet and the electromagnetic coil.
 17. Theliquid feeding device according to claim 16, wherein the damping elementis made out of silicone.
 18. The liquid feeding device according toclaim 1, wherein the membrane is a stainless steel membrane.
 19. Theliquid feeding device according to claim 1, wherein the droplet ejectionsection comprises an actuation portion and a nozzle portion, theactuation portion comprising at least the excitation unit, and thenozzle portion comprising at least the at least one inlet port, theliquid chamber, the nozzle and the membrane.
 20. The liquid feedingdevice according to claim 19, wherein the nozzle portion comprises anozzle portion main body and a nozzle body provided separately from thenozzle portion main body.
 21. The liquid feeding device according toclaim 20, wherein the nozzle body is permanently installed in a centralthrough-hole in the nozzle portion main body.
 22. The liquid feedingdevice according to claim 21, wherein the nozzle body is permanentlyinstalled in a central through-hole in the nozzle portion main body bylaser welding.
 23. The liquid feeding device according to claim 19,wherein the membrane is welded to the nozzle portion for airtightlyclosing the liquid chamber on one side.
 24. The liquid feeding deviceaccording to claim 23, wherein the membrane is welded to the nozzleportion for airtightly closing the liquid chamber on one side by laserwelding.
 25. The liquid feeding device according to claim 1, furthercomprising a CiP/SiP section arranged between the droplet ejectionsection and the deflection section, for providing CiP fluid and/or SiPfluid to the parts of the liquid feeding device subsequent to thedroplet ejection section.
 26. The liquid feeding device according toclaim 1, further comprising a droplet counting section for counting thedroplets.
 27. The liquid feeding device according to claim 26, whereinthe droplet counting section for counting the droplets is providedbefore the deflection section in the ejection direction of the liquid.28. A process line for the production of freeze-dried particles for thepharmaceutical field, comprising a liquid feeding device according toclaim 1, for the generation of droplets, a freezing chamber forfreeze-congealing droplets fed from the liquid feeding device, and afreeze-dryer for lyophilization of the frozen droplets.
 29. A processfor preparing a vaccine composition comprising one or more antigens inthe form of freeze-dried particles comprising at least a step ofgenerating liquid droplets of said vaccine composition with a liquidfeeding device according to claim
 1. 30. The process according to claim29, wherein all the steps are carried out under sterile conditions. 31.The process according to claim 29, wherein the freeze-dried particlesare sterile.
 32. A process for preparing an adjuvant containing vaccinecomposition comprising one or more antigens in the form of freeze-driedparticles comprising: at least a step of generating liquid droplets ofsaid vaccine composition with the liquid feeding device according toclaim 1, or at least the steps of generating liquid droplets of anantigen(s)-containing composition with the liquid feeding deviceaccording to claim 1, of generating liquid droplets of anadjuvant-containing composition with the liquid feeding device accordingto claim 1, freeze-drying the droplets to obtain freeze-dried particles,and blending the freeze-dried particles of antigen(s) with thefreeze-dried particles of adjuvant.
 33. The liquid feeding device forthe generation of droplets for the use in a process line for theproduction of freeze-dried particles for the pharmaceutical field, witha droplet ejection section for ejecting liquid droplets in an ejectiondirection, the droplet ejection section comprising at least one inletport for receiving a liquid to be ejected, a liquid chamber forretaining the liquid, and a fixed nozzle directed vertically forejecting the liquid from the liquid chamber vertically to form dropletsthat travel along a vertical ejection path, wherein the liquid chamberis restricted by a membrane on one side thereof, the membrane beingvibratable by an excitation unit, and wherein the longitudinal axis ofthe liquid chamber is tilted relative to the longitudinal axis of thenozzle.